Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors
Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors
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DOI：
10.1200/jco.2008.19.6683
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发表时间：
2009-07-20
影响因子：
45.3
通讯作者：
Rosen, Lee S.
中科院分区：
文献类型：
--
作者：
Herbst, Roy S.;Hong, David;Rosen, Lee S.
目的AMG 386是一种正在研究的多肽-Fc融合蛋白(即多肽抗体)，它通过阻止血管生成素-1和血管生成素-2与其受体Tie2的相互作用来抑制血管生成。这项首次人体研究评估了AMG 386在成人晚期实体瘤患者中的安全性、药代动力学(PK)、药效学和抗肿瘤活性。患者和方法序贯队列患者每周静脉注射AMG 386 0.3、1、3、10或30 mg/kg。结果32名患者入选研究，接受AMG 386治疗。剂量限制性毒性的一次发生在30 mg/kg：呼吸停止，这可能是由可能与AMG 386有关的肿瘤负担引起的。最常见的毒副反应是乏力和外周水肿。11例出现蛋白尿，无临床后遗症。只有4名患者(12%)经历了与治疗相关的毒性超过1级。没有达到最大耐受剂量。PK呈剂量线性关系，平均终末消除半衰期为3.1~6.3天。每周服药4次后，血清AMG386水平似乎达到稳定状态，并有很小的蓄积。未检测到抗AMG386中和抗体。在治疗后48小时至8周，观察到10名患者(13个病灶)的容量转移常数(K-TRANS；通过动态增强磁共振成像测量)降低。1例难治性卵巢癌患者经156周治疗后部分缓解(实体瘤有效率下降32.5%)，4例患者病情稳定至少16周。结论AMG386每周给药耐受性良好，安全性与血管内皮生长因子轴抑制剂不同。AMG386似乎也影响肿瘤血管，并在该患者群体中显示出抗肿瘤活性。
PurposeAMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors.Patients and MethodsPatients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg.ResultsThirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti-AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (K-trans; measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks.ConclusionWeekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor-axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient population.